Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

Miriam Iannicelli; Francesco Brancati; Soumaya Mougou-Zerelli; Annalisa Mazzotta; Sophie Thomas; Nadia Elkhartoufi; Lorena Travaglini; Céline Gomes; Gian Luigi Ardissino; Enrico Bertini; Eugen Boltshauser; Pierangela Castorina; Stefano D'Arrigo; Rita Fischetto; Brigitte Leroy; Philippe Loget; Maryse Bonnière; Lena Starck; Julia Tantau; Barbara Gentilin; Silvia Majore; Dominika Swistun; Elizabeth Flori; Faustina Lalatta; Chiara Pantaleoni; Johannes Penzien; Paola Grammatico; Bruno Dallapiccola; Joseph G. Gleeson; Tania Attie-Bitach; Enza Maria Valente; L. Ali Pacha; M. Tazir; A. Zankl; R. Leventer; P. Grattan-Smith; A. Janecke; M. D'Hooghe; Y. Sznajer; R. Van Coster; L. Demerleir; K. Dias; C. Moco; A. Moreira; C. Ae Kim; G. Maegawa; D. Loncarevic; V. Mejaski-Bosnjak; D. Petkovic; G. M.H. Abdel-Salam; A. Abdel-Aleem; M. S. Zaki; I. Marti; S. Quijano-Roy; S. Sigaudy; P. De Lonlay; S. Romano; A. Verloes; R. Touraine; M. Koenig; C. Lagier-Tourenne; J. Messer; P. Collignon; N. Wolf; H. Philippi; J. Lemke; C. Dacou-Voutetakis; S. Kitsiou Tzeli; R. Pons; L. Sztriha; S. Halldorsson; J. Johannsdottir; P. Ludvigsson; S. R. Phadke; V. Udani; B. Stuart; A. Magee; D. Lev; M. Michelson; B. Ben-Zeev; M. Di Giacomo; M. Gentile; G. Guanti; O. D'Addato; F. Papadia; M. Spano; F. Bernardi; M. Seri; F. Benedicenti; F. Stanzial; R. Borgatti; P. Accorsi; S. Battaglia; E. Fazzi; L. Giordano; C. Izzi; L. Pinelli; L. Boccone; P. Guanciali; R. Romoli; S. Bigoni; A. Ferlini; E. Andreucci; M. A. Donati; M. Genuardi; G. Caridi; M. T. Divizia; F. Faravelli; G. Ghiggeri; A. Pessagno; M. Amorini; M. Briguglio; S. Briuglia; L. Rigoli; C. Salpietro; G. Tortorella; A. Adami; G. Marra; D. Riva; B. Scelsa; L. Spaccini; G. Uziel; G. Coppola; E. Del Giudice; G. Vitiello; A. M. Laverda; K. Ludwig; A. Permunian; A. Suppiej; C. Macaluso; S. Signorini; C. Uggetti; R. Battini; M. Di Giacomo; M. Priolo; M. R. Cilio; A. D'Amico; M. L. Di Sabato; F. Emma; V. Leuzzi; P. Parisi; G. Stringini; G. Zanni; M. Pollazzon; A. Renieri; M. Vascotto; M. Silengo; R. De Vescovi; D. Greco; C. Romano; M. Cazzagon; A. Simonati; A. A. Al-Tawari; L. Bastaki; A. Mégarbané; A. Matuleviciene; V. Sabolic Avramovska; E. Said; M. M. De Jong; T. Prescott; P. Stromme; C. Von Der Lippe; R. Koul; A. Rajab; M. Azam; C. Barbot; B. Jocic-Jakubi; B. Gener Querol; L. Martorell Sampol; B. Rodriguez; I. Pascual-Castroviejo; S. Strozzi; J. Fluss; S. Teber M; Topcu; B. Anlar; S. Comu; E. Karaca; H. Kayserili; A. Yüksel; M. Akgul; M. Akcakus; L. Al Gazali; D. Nicholl; C. G. Woods; C. Bennett; J. Hurst; E. Sheridan; A. Barnicoat; L. Carr; R. Hennekam; M. Lees; F. McKay; L. Yates; E. Blair; S. Bernes; H. Sanchez; A. E. Clark; E. DeMarco; C. Donahue; E. Sherr; J. Hahn; T. D. Sanger; T. E. Gallager; W. B. Dobyns; C. Daugherty; K. S. Krishnamoorthy; D. Sarco; C. A. Walsh; T. McKanna; J. Milisa; W. K. Chung; D. C. De Vivo; H. Raynes; R. Schubert; A. Seward; D. G. Brooks; A. Goldstein; J. Caldwell; E. Finsecke; B. L. Maria; K. Holden; R. P. Cruse; K. J. Swoboda; D. Viskochil

doi:10.1002/humu.21239

Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

Miriam Iannicelli, Francesco Brancati, Soumaya Mougou-Zerelli, Annalisa Mazzotta, Sophie Thomas, Nadia Elkhartoufi, Lorena Travaglini, Céline Gomes, Gian Luigi Ardissino, Enrico Bertini, Eugen Boltshauser, Pierangela Castorina, Stefano D'Arrigo, Rita Fischetto, Brigitte Leroy, Philippe Loget, Maryse Bonnière, Lena Starck, Julia Tantau, Barbara GentilinSilvia Majore, Dominika Swistun, Elizabeth Flori, Faustina Lalatta, Chiara Pantaleoni, Johannes Penzien, Paola Grammatico, Bruno Dallapiccola, Joseph G. Gleeson, Tania Attie-Bitach, Enza Maria Valente, L. Ali Pacha, M. Tazir, A. Zankl, R. Leventer, P. Grattan-Smith, A. Janecke, M. D'Hooghe, Y. Sznajer, R. Van Coster, L. Demerleir, K. Dias, C. Moco, A. Moreira, C. Ae Kim, G. Maegawa, D. Loncarevic, V. Mejaski-Bosnjak, D. Petkovic, G. M.H. Abdel-Salam, A. Abdel-Aleem, M. S. Zaki, I. Marti, S. Quijano-Roy, S. Sigaudy, P. De Lonlay, S. Romano, A. Verloes, R. Touraine, M. Koenig, C. Lagier-Tourenne, J. Messer, P. Collignon, N. Wolf, H. Philippi, J. Lemke, C. Dacou-Voutetakis, S. Kitsiou Tzeli, R. Pons, L. Sztriha, S. Halldorsson, J. Johannsdottir, P. Ludvigsson, S. R. Phadke, V. Udani, B. Stuart, A. Magee, D. Lev, M. Michelson, B. Ben-Zeev, M. Di Giacomo, M. Gentile, G. Guanti, O. D'Addato, F. Papadia, M. Spano, F. Bernardi, M. Seri, F. Benedicenti, F. Stanzial, R. Borgatti, P. Accorsi, S. Battaglia, E. Fazzi, L. Giordano, C. Izzi, L. Pinelli, L. Boccone, P. Guanciali, R. Romoli, S. Bigoni, A. Ferlini, E. Andreucci, M. A. Donati, M. Genuardi, G. Caridi, M. T. Divizia, F. Faravelli, G. Ghiggeri, A. Pessagno, M. Amorini, M. Briguglio, S. Briuglia, L. Rigoli, C. Salpietro, G. Tortorella, A. Adami, G. Marra, D. Riva, B. Scelsa, L. Spaccini, G. Uziel, G. Coppola, E. Del Giudice, G. Vitiello, A. M. Laverda, K. Ludwig, A. Permunian, A. Suppiej, C. Macaluso, S. Signorini, C. Uggetti, R. Battini, M. Di Giacomo, M. Priolo, M. R. Cilio, A. D'Amico, M. L. Di Sabato, F. Emma, V. Leuzzi, P. Parisi, G. Stringini, G. Zanni, M. Pollazzon, A. Renieri, M. Vascotto, M. Silengo, R. De Vescovi, D. Greco, C. Romano, M. Cazzagon, A. Simonati, A. A. Al-Tawari, L. Bastaki, A. Mégarbané, A. Matuleviciene, V. Sabolic Avramovska, E. Said, M. M. De Jong, T. Prescott, P. Stromme, C. Von Der Lippe, R. Koul, A. Rajab, M. Azam, C. Barbot, B. Jocic-Jakubi, B. Gener Querol, L. Martorell Sampol, B. Rodriguez, I. Pascual-Castroviejo, S. Strozzi, J. Fluss, S. Teber M, Topcu, B. Anlar, S. Comu, E. Karaca, H. Kayserili, A. Yüksel, M. Akgul, M. Akcakus, L. Al Gazali, D. Nicholl, C. G. Woods, C. Bennett, J. Hurst, E. Sheridan, A. Barnicoat, L. Carr, R. Hennekam, M. Lees, F. McKay, L. Yates, E. Blair, S. Bernes, H. Sanchez, A. E. Clark, E. DeMarco, C. Donahue, E. Sherr, J. Hahn, T. D. Sanger, T. E. Gallager, W. B. Dobyns, C. Daugherty, K. S. Krishnamoorthy, D. Sarco, C. A. Walsh, T. McKanna, J. Milisa, W. K. Chung, D. C. De Vivo, H. Raynes, R. Schubert, A. Seward, D. G. Brooks, A. Goldstein, J. Caldwell, E. Finsecke, B. L. Maria, K. Holden, R. P. Cruse, K. J. Swoboda, D. Viskochil

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

Original language	English (US)
Pages (from-to)	E1319-E1331
Journal	Human mutation
Volume	31
Issue number	5
DOIs	https://doi.org/10.1002/humu.21239
State	Published - May 2010
Externally published	Yes

Keywords

COACH syndrome
Congenital hepatic fibrosis
Joubert syndrome
MKS3
Meckel syndrome
TMEM67

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/humu.21239

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Iannicelli, M., Brancati, F., Mougou-Zerelli, S., Mazzotta, A., Thomas, S., Elkhartoufi, N., Travaglini, L., Gomes, C., Ardissino, G. L., Bertini, E., Boltshauser, E., Castorina, P., D'Arrigo, S., Fischetto, R., Leroy, B., Loget, P., Bonnière, M., Starck, L., Tantau, J., ... Viskochil, D. (2010). Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. Human mutation, 31(5), E1319-E1331. https://doi.org/10.1002/humu.21239

Iannicelli, M, Brancati, F, Mougou-Zerelli, S, Mazzotta, A, Thomas, S, Elkhartoufi, N, Travaglini, L, Gomes, C, Ardissino, GL, Bertini, E, Boltshauser, E, Castorina, P, D'Arrigo, S, Fischetto, R, Leroy, B, Loget, P, Bonnière, M, Starck, L, Tantau, J, Gentilin, B, Majore, S, Swistun, D, Flori, E, Lalatta, F, Pantaleoni, C, Penzien, J, Grammatico, P, Dallapiccola, B, Gleeson, JG, Attie-Bitach, T, Valente, EM, Ali Pacha, L, Tazir, M, Zankl, A, Leventer, R, Grattan-Smith, P, Janecke, A, D'Hooghe, M, Sznajer, Y, Van Coster, R, Demerleir, L, Dias, K, Moco, C, Moreira, A, Ae Kim, C, Maegawa, G, Loncarevic, D, Mejaski-Bosnjak, V, Petkovic, D, Abdel-Salam, GMH, Abdel-Aleem, A, Zaki, MS, Marti, I, Quijano-Roy, S, Sigaudy, S, De Lonlay, P, Romano, S, Verloes, A, Touraine, R, Koenig, M, Lagier-Tourenne, C, Messer, J, Collignon, P, Wolf, N, Philippi, H, Lemke, J, Dacou-Voutetakis, C, Kitsiou Tzeli, S, Pons, R, Sztriha, L, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Phadke, SR, Udani, V, Stuart, B, Magee, A, Lev, D, Michelson, M, Ben-Zeev, B, Di Giacomo, M, Gentile, M, Guanti, G, D'Addato, O, Papadia, F, Spano, M, Bernardi, F, Seri, M, Benedicenti, F, Stanzial, F, Borgatti, R, Accorsi, P, Battaglia, S, Fazzi, E, Giordano, L, Izzi, C, Pinelli, L, Boccone, L, Guanciali, P, Romoli, R, Bigoni, S, Ferlini, A, Andreucci, E, Donati, MA, Genuardi, M, Caridi, G, Divizia, MT, Faravelli, F, Ghiggeri, G, Pessagno, A, Amorini, M, Briguglio, M, Briuglia, S, Rigoli, L, Salpietro, C, Tortorella, G, Adami, A, Marra, G, Riva, D, Scelsa, B, Spaccini, L, Uziel, G, Coppola, G, Del Giudice, E, Vitiello, G, Laverda, AM, Ludwig, K, Permunian, A, Suppiej, A, Macaluso, C, Signorini, S, Uggetti, C, Battini, R, Di Giacomo, M, Priolo, M, Cilio, MR, D'Amico, A, Di Sabato, ML, Emma, F, Leuzzi, V, Parisi, P, Stringini, G, Zanni, G, Pollazzon, M, Renieri, A, Vascotto, M, Silengo, M, De Vescovi, R, Greco, D, Romano, C, Cazzagon, M, Simonati, A, Al-Tawari, AA, Bastaki, L, Mégarbané, A, Matuleviciene, A, Sabolic Avramovska, V, Said, E, De Jong, MM, Prescott, T, Stromme, P, Von Der Lippe, C, Koul, R, Rajab, A, Azam, M, Barbot, C, Jocic-Jakubi, B, Gener Querol, B, Martorell Sampol, L, Rodriguez, B, Pascual-Castroviejo, I, Strozzi, S, Fluss, J, Teber M, S, Topcu, Anlar, B, Comu, S, Karaca, E, Kayserili, H, Yüksel, A, Akgul, M, Akcakus, M, Al Gazali, L, Nicholl, D, Woods, CG, Bennett, C, Hurst, J, Sheridan, E, Barnicoat, A, Carr, L, Hennekam, R, Lees, M, McKay, F, Yates, L, Blair, E, Bernes, S, Sanchez, H, Clark, AE, DeMarco, E, Donahue, C, Sherr, E, Hahn, J, Sanger, TD, Gallager, TE, Dobyns, WB, Daugherty, C, Krishnamoorthy, KS, Sarco, D, Walsh, CA, McKanna, T, Milisa, J, Chung, WK, De Vivo, DC, Raynes, H, Schubert, R, Seward, A, Brooks, DG, Goldstein, A, Caldwell, J, Finsecke, E, Maria, BL, Holden, K, Cruse, RP, Swoboda, KJ & Viskochil, D 2010, 'Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies', Human mutation, vol. 31, no. 5, pp. E1319-E1331. https://doi.org/10.1002/humu.21239

@article{a7555be970024d70b9b40e4f743dbade,

title = "Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies",

abstract = "Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.",

keywords = "COACH syndrome, Congenital hepatic fibrosis, Joubert syndrome, MKS3, Meckel syndrome, TMEM67",

author = "Miriam Iannicelli and Francesco Brancati and Soumaya Mougou-Zerelli and Annalisa Mazzotta and Sophie Thomas and Nadia Elkhartoufi and Lorena Travaglini and C{\'e}line Gomes and Ardissino, {Gian Luigi} and Enrico Bertini and Eugen Boltshauser and Pierangela Castorina and Stefano D'Arrigo and Rita Fischetto and Brigitte Leroy and Philippe Loget and Maryse Bonni{\`e}re and Lena Starck and Julia Tantau and Barbara Gentilin and Silvia Majore and Dominika Swistun and Elizabeth Flori and Faustina Lalatta and Chiara Pantaleoni and Johannes Penzien and Paola Grammatico and Bruno Dallapiccola and Gleeson, {Joseph G.} and Tania Attie-Bitach and Valente, {Enza Maria} and {Ali Pacha}, L. and M. Tazir and A. Zankl and R. Leventer and P. Grattan-Smith and A. Janecke and M. D'Hooghe and Y. Sznajer and {Van Coster}, R. and L. Demerleir and K. Dias and C. Moco and A. Moreira and {Ae Kim}, C. and G. Maegawa and D. Loncarevic and V. Mejaski-Bosnjak and D. Petkovic and Abdel-Salam, {G. M.H.} and A. Abdel-Aleem and Zaki, {M. S.} and I. Marti and S. Quijano-Roy and S. Sigaudy and {De Lonlay}, P. and S. Romano and A. Verloes and R. Touraine and M. Koenig and C. Lagier-Tourenne and J. Messer and P. Collignon and N. Wolf and H. Philippi and J. Lemke and C. Dacou-Voutetakis and {Kitsiou Tzeli}, S. and R. Pons and L. Sztriha and S. Halldorsson and J. Johannsdottir and P. Ludvigsson and Phadke, {S. R.} and V. Udani and B. Stuart and A. Magee and D. Lev and M. Michelson and B. Ben-Zeev and {Di Giacomo}, M. and M. Gentile and G. Guanti and O. D'Addato and F. Papadia and M. Spano and F. Bernardi and M. Seri and F. Benedicenti and F. Stanzial and R. Borgatti and P. Accorsi and S. Battaglia and E. Fazzi and L. Giordano and C. Izzi and L. Pinelli and L. Boccone and P. Guanciali and R. Romoli and S. Bigoni and A. Ferlini and E. Andreucci and Donati, {M. A.} and M. Genuardi and G. Caridi and Divizia, {M. T.} and F. Faravelli and G. Ghiggeri and A. Pessagno and M. Amorini and M. Briguglio and S. Briuglia and L. Rigoli and C. Salpietro and G. Tortorella and A. Adami and G. Marra and D. Riva and B. Scelsa and L. Spaccini and G. Uziel and G. Coppola and {Del Giudice}, E. and G. Vitiello and Laverda, {A. M.} and K. Ludwig and A. Permunian and A. Suppiej and C. Macaluso and S. Signorini and C. Uggetti and R. Battini and {Di Giacomo}, M. and M. Priolo and Cilio, {M. R.} and A. D'Amico and {Di Sabato}, {M. L.} and F. Emma and V. Leuzzi and P. Parisi and G. Stringini and G. Zanni and M. Pollazzon and A. Renieri and M. Vascotto and M. Silengo and {De Vescovi}, R. and D. Greco and C. Romano and M. Cazzagon and A. Simonati and Al-Tawari, {A. A.} and L. Bastaki and A. M{\'e}garban{\'e} and A. Matuleviciene and {Sabolic Avramovska}, V. and E. Said and {De Jong}, {M. M.} and T. Prescott and P. Stromme and {Von Der Lippe}, C. and R. Koul and A. Rajab and M. Azam and C. Barbot and B. Jocic-Jakubi and {Gener Querol}, B. and {Martorell Sampol}, L. and B. Rodriguez and I. Pascual-Castroviejo and S. Strozzi and J. Fluss and {Teber M}, S. and Topcu and B. Anlar and S. Comu and E. Karaca and H. Kayserili and A. Y{\"u}ksel and M. Akgul and M. Akcakus and {Al Gazali}, L. and D. Nicholl and Woods, {C. G.} and C. Bennett and J. Hurst and E. Sheridan and A. Barnicoat and L. Carr and R. Hennekam and M. Lees and F. McKay and L. Yates and E. Blair and S. Bernes and H. Sanchez and Clark, {A. E.} and E. DeMarco and C. Donahue and E. Sherr and J. Hahn and Sanger, {T. D.} and Gallager, {T. E.} and Dobyns, {W. B.} and C. Daugherty and Krishnamoorthy, {K. S.} and D. Sarco and Walsh, {C. A.} and T. McKanna and J. Milisa and Chung, {W. K.} and {De Vivo}, {D. C.} and H. Raynes and R. Schubert and A. Seward and Brooks, {D. G.} and A. Goldstein and J. Caldwell and E. Finsecke and Maria, {B. L.} and K. Holden and Cruse, {R. P.} and Swoboda, {K. J.} and D. Viskochil",

year = "2010",

month = may,

doi = "10.1002/humu.21239",

language = "English (US)",

volume = "31",

pages = "E1319--E1331",

journal = "Human mutation",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

number = "5",

}

TY - JOUR

T1 - Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

AU - Iannicelli, Miriam

AU - Brancati, Francesco

AU - Mougou-Zerelli, Soumaya

AU - Mazzotta, Annalisa

AU - Thomas, Sophie

AU - Elkhartoufi, Nadia

AU - Travaglini, Lorena

AU - Gomes, Céline

AU - Ardissino, Gian Luigi

AU - Bertini, Enrico

AU - Boltshauser, Eugen

AU - Castorina, Pierangela

AU - D'Arrigo, Stefano

AU - Fischetto, Rita

AU - Leroy, Brigitte

AU - Loget, Philippe

AU - Bonnière, Maryse

AU - Starck, Lena

AU - Tantau, Julia

AU - Gentilin, Barbara

AU - Majore, Silvia

AU - Swistun, Dominika

AU - Flori, Elizabeth

AU - Lalatta, Faustina

AU - Pantaleoni, Chiara

AU - Penzien, Johannes

AU - Grammatico, Paola

AU - Dallapiccola, Bruno

AU - Gleeson, Joseph G.

AU - Attie-Bitach, Tania

AU - Valente, Enza Maria

AU - Ali Pacha, L.

AU - Tazir, M.

AU - Zankl, A.

AU - Leventer, R.

AU - Grattan-Smith, P.

AU - Janecke, A.

AU - D'Hooghe, M.

AU - Sznajer, Y.

AU - Van Coster, R.

AU - Demerleir, L.

AU - Dias, K.

AU - Moco, C.

AU - Moreira, A.

AU - Ae Kim, C.

AU - Maegawa, G.

AU - Loncarevic, D.

AU - Mejaski-Bosnjak, V.

AU - Petkovic, D.

AU - Abdel-Salam, G. M.H.

AU - Abdel-Aleem, A.

AU - Zaki, M. S.

AU - Marti, I.

AU - Quijano-Roy, S.

AU - Sigaudy, S.

AU - De Lonlay, P.

AU - Romano, S.

AU - Verloes, A.

AU - Touraine, R.

AU - Koenig, M.

AU - Lagier-Tourenne, C.

AU - Messer, J.

AU - Collignon, P.

AU - Wolf, N.

AU - Philippi, H.

AU - Lemke, J.

AU - Dacou-Voutetakis, C.

AU - Kitsiou Tzeli, S.

AU - Pons, R.

AU - Sztriha, L.

AU - Halldorsson, S.

AU - Johannsdottir, J.

AU - Ludvigsson, P.

AU - Phadke, S. R.

AU - Udani, V.

AU - Stuart, B.

AU - Magee, A.

AU - Lev, D.

AU - Michelson, M.

AU - Ben-Zeev, B.

AU - Di Giacomo, M.

AU - Gentile, M.

AU - Guanti, G.

AU - D'Addato, O.

AU - Papadia, F.

AU - Spano, M.

AU - Bernardi, F.

AU - Seri, M.

AU - Benedicenti, F.

AU - Stanzial, F.

AU - Borgatti, R.

AU - Accorsi, P.

AU - Battaglia, S.

AU - Fazzi, E.

AU - Giordano, L.

AU - Izzi, C.

AU - Pinelli, L.

AU - Boccone, L.

AU - Guanciali, P.

AU - Romoli, R.

AU - Bigoni, S.

AU - Ferlini, A.

AU - Andreucci, E.

AU - Donati, M. A.

AU - Genuardi, M.

AU - Caridi, G.

AU - Divizia, M. T.

AU - Faravelli, F.

AU - Ghiggeri, G.

AU - Pessagno, A.

AU - Amorini, M.

AU - Briguglio, M.

AU - Briuglia, S.

AU - Rigoli, L.

AU - Salpietro, C.

AU - Tortorella, G.

AU - Adami, A.

AU - Marra, G.

AU - Riva, D.

AU - Scelsa, B.

AU - Spaccini, L.

AU - Uziel, G.

AU - Coppola, G.

AU - Del Giudice, E.

AU - Vitiello, G.

AU - Laverda, A. M.

AU - Ludwig, K.

AU - Permunian, A.

AU - Suppiej, A.

AU - Macaluso, C.

AU - Signorini, S.

AU - Uggetti, C.

AU - Battini, R.

AU - Di Giacomo, M.

AU - Priolo, M.

AU - Cilio, M. R.

AU - D'Amico, A.

AU - Di Sabato, M. L.

AU - Emma, F.

AU - Leuzzi, V.

AU - Parisi, P.

AU - Stringini, G.

AU - Zanni, G.

AU - Pollazzon, M.

AU - Renieri, A.

AU - Vascotto, M.

AU - Silengo, M.

AU - De Vescovi, R.

AU - Greco, D.

AU - Romano, C.

AU - Cazzagon, M.

AU - Simonati, A.

AU - Al-Tawari, A. A.

AU - Bastaki, L.

AU - Mégarbané, A.

AU - Matuleviciene, A.

AU - Sabolic Avramovska, V.

AU - Said, E.

AU - De Jong, M. M.

AU - Prescott, T.

AU - Stromme, P.

AU - Von Der Lippe, C.

AU - Koul, R.

AU - Rajab, A.

AU - Azam, M.

AU - Barbot, C.

AU - Jocic-Jakubi, B.

AU - Gener Querol, B.

AU - Martorell Sampol, L.

AU - Rodriguez, B.

AU - Pascual-Castroviejo, I.

AU - Strozzi, S.

AU - Fluss, J.

AU - Teber M, S.

AU - Topcu,

AU - Anlar, B.

AU - Comu, S.

AU - Karaca, E.

AU - Kayserili, H.

AU - Yüksel, A.

AU - Akgul, M.

AU - Akcakus, M.

AU - Al Gazali, L.

AU - Nicholl, D.

AU - Woods, C. G.

AU - Bennett, C.

AU - Hurst, J.

AU - Sheridan, E.

AU - Barnicoat, A.

AU - Carr, L.

AU - Hennekam, R.

AU - Lees, M.

AU - McKay, F.

AU - Yates, L.

AU - Blair, E.

AU - Bernes, S.

AU - Sanchez, H.

AU - Clark, A. E.

AU - DeMarco, E.

AU - Donahue, C.

AU - Sherr, E.

AU - Hahn, J.

AU - Sanger, T. D.

AU - Gallager, T. E.

AU - Dobyns, W. B.

AU - Daugherty, C.

AU - Krishnamoorthy, K. S.

AU - Sarco, D.

AU - Walsh, C. A.

AU - McKanna, T.

AU - Milisa, J.

AU - Chung, W. K.

AU - De Vivo, D. C.

AU - Raynes, H.

AU - Schubert, R.

AU - Seward, A.

AU - Brooks, D. G.

AU - Goldstein, A.

AU - Caldwell, J.

AU - Finsecke, E.

AU - Maria, B. L.

AU - Holden, K.

AU - Cruse, R. P.

AU - Swoboda, K. J.

AU - Viskochil, D.

PY - 2010/5

Y1 - 2010/5

N2 - Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

AB - Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

KW - COACH syndrome

KW - Congenital hepatic fibrosis

KW - Joubert syndrome

KW - MKS3

KW - Meckel syndrome

KW - TMEM67

UR - http://www.scopus.com/inward/record.url?scp=77951821478&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951821478&partnerID=8YFLogxK

U2 - 10.1002/humu.21239

DO - 10.1002/humu.21239

M3 - Article

C2 - 20232449

AN - SCOPUS:77951821478

SN - 1059-7794

VL - 31

SP - E1319-E1331

JO - Human mutation

JF - Human mutation

IS - 5

ER -

Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

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